Journal:JBSD:35

A Possible Strategy against Head and Neck Cancer: In Silico. Investigation of Three-in-One inhibitors

Yung-An Tsou, Kuan-Chung Chen, Su-Sen Chang, Yeong-Ray Wen, Calvin Yu-Chian Chen ^[1]

Molecular Tour
Uroporphyrinogen decarboxylase (UROD) (colored in darkmagenta), which is an enzyme with decarboxylation reaction of uroporphyrinogen III to coproporphyrinogen III (colored in salmon), is overexpressed in tumor tissues and has potential to sensitize cancer patients to radiotherapy. Moreover, epidermal growth factor receptor (EGFR) (colored in magenta) and human epidermal growth factor receptor 2 (Her2) (colored in deeppink), which are tyrosine kinase receptors in the erbB family, are also overexpressed in tumor tissues and have been indicated as the important targets of therapy for cancer. In this research, we discuss the possible conformation for an inhibitor against three target proteins, UROD, EGFR, and Her2.

Virtual screening of the UROD (PDB ID: 1r3y), EGFR (PDB ID: 3poz), and Her2 (PDB ID: 3pp0) was conducted using the binding site defined by the volume and location of the co-crystallized compounds in each crystal structure. In silico results indicate the traditional Chinese medicine (TCM) compounds had high binding affinity with all three target protein. For EGFR protein (colored in magenta), the top three compounds, eicosanedioic acid (colored in yellow), docosanedioic acid (colored in cyan), and norbixin (colored in orange), formed hydrogen bonds with the residues, Arg803, Lys913 and some other residues in the binding domain. The docking poses of Her2 protein (colored in deeppink) with eicosanedioic acid (colored in yellow), docosanedioic acid (colored in cyan), and norbixin (colored in orange), exhibited hydrogen bonds between ligands and the residues in the binding site. For UROD protein (colored in darkmagenta), eicosanedioic acid (colored in yellow), docosanedioic acid (colored in cyan), and norbixin (colored in orange), have hydrogen bonds with the three important binding and catalytic residues Arg37, Arg41, Tyr164, and the residue His220. The three TCM compounds hint towards a probable molecule backbone which might be used to evolve drug-like compounds against EGFR, Her2, and UROD, and have potential application against head and neck cancer.